Progressive, irreversible, neuronal damage already has occurred by the time clinical symptoms of Alzheimer disease (AD) are documented. However, biochemical, histopathological and gross anatomic features of AD begin to appear during its insidious onset, preceding dementia by decades. Because of their value for diagnosis, screening, prognosis and as endpoints in clinical trials, enormous effort is being expended to define and detect early markers of AD, particularly utilizing established medical imaging approaches such as MRI and PET, and mildly invasive approaches such as lumbar puncture. However, a suitable tool for early diagnosis of MCI subjects who are likely convert to AD is non-invasive and can be routinely used at the point of care. Also, next generation drugs targeting the root causes of AD will need to identify and recruit subjects at very early stages of the disease, who otherwise will convert to advanced stage AD, because treatment, if successful, needs to start early, preferably in patients with mild cognitive impairment (MCI) due to AD or even asymptomatic subjects at the preclinical phase - again calling for practicable screening at the point of care. Currently, no clinically approved biomarker or imaging tool is available to identify such patients. The ability to identify MCI subjects who wil likely convert to AD and differentiate them from MCI non-converters will enable selection of the MCI converters as the most effective cohort for evaluating efficacy of trial therapeutics and will enable treatment, when available, at the earliest, most effective, stage of the disease. This proposal is to advance a relatively inexpensive, widely deployable and non-invasive approach for early detection at-point-of-care and progress monitoring of AD. Using technology developed under prior Merit funding, we show that near-infrared optical spectroscopy (NIR) can differentiate AD, MCI (mild cognitive impairment) and control patients. However, not all MCI patients convert to full blown AD. Near infrared light can propagate several centimeters through living tissue to reach the brain, completely non-invasively. Their inherent physical-chemical properties make plaques and tangles detectable optically, without stains or labels: they are dense protein aggregates, which scatter light characteristically. Thus, a direct connection between the observed NIR optical spectra and the known neuropathological features of disease is provided, in vivo. On the other hand, in the absence of biopsy and pathology, biological markers are the most direct diagnostic link to underlying disease. The concentration ratios of amyloid beta peptides to tau proteins in cerebrospinal fluid has emerged as the most clinically validated and quantified prognostic marker for AD to date. However, CSF collection is invasive and is not a routine practice for asymptomatic subjects. Herein we propose to demonstrate that NIR spectroscopy can provide a non- invasive, more readily accessible and equally accurate screen for incipient AD, while at the same time providing information complementary to MRI and PET.